Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy

Abstract

There are well-known side effects of chemotherapy and radiotherapy that are mainly related to the toxicity and impaired function of vital organs; however, the induction by these therapies of expression of several pro-metastatic factors in various tissues and organs that in toto create a pro-metastatic microenvironment is still, surprisingly, not widely acknowledged. In this review, we support the novel concept that toxic damage in various organs leads to upregulation in "bystander" tissues of several factors such as chemokines, growth factors, alarmines, and bioactive phosphosphingolipids, which attract circulating normal stem cells for regeneration but unfortunately also provide chemotactic signals to cancer cells that survived the initial treatment. We propose that this mechanism plays an important role in the metastasis of cancer cells to organs such as bones, lungs, and liver, which are highly susceptible to chemotherapeutic agents as well as ionizing irradiation. This problem indicates the need to develop efficient anti-metastatic drugs that will work in combination with, or follow, standard therapies in order to prevent the possibility of therapy-induced spread of tumor cells.

Keywords: Alarmines; C1P; CXCR4; Cancer metastasis; Chemotherapy; Radiotherapy; S1P; SDF-1; Side effects.

Figure 1

Chemotherapy or radiotherapy induces a metastasis-receptive microenvironment in various organs. One of the unwanted side effects of treatment is upregulation of several pro-metastatic and pro-survival factors, such as chemokines (e.g., SDF-1), growth factors (HGF/SF and VEGF), bioactive sphigophospholipids (S1P and C1P), and alarmines (ATP and UTP) in collateral-damaged tissues and organs. In parallel, in response to tissue damage, proteolytic cascades, such as the coagulation cascade (CoaC), complement cascade (ComC), and fibrynolytic cascade (FibC), are activated, which in different ways also enhance the metastasis of cancer cells that survived treatment. These most-resistant-to-therapy, and thus surviving, cancer cells are usually endowed with high endogenous motility. This mechanism plays an important role, primarily in metastasis of malignant cells to the tissues susceptible to the toxic effects of chemotherapy or radiotherapy, such as bones, lungs, liver and abdominal and pelvic cavities.

Figure 2

Chemotherapy- or radiotherapy-mediated metastasis of cancer cells to bones. Due to upregulation of several homing and pro-survival factors in response to BM microenvironment damage, circulating cancer cells may find a permissive environment in BM, which can originate growth of a bone metastasis. Similar mechanism may also operate in pelvic cavity after chemotherapy and lead to spread of ovarian cancer.

Figure 3

Increase in expression of important chemoattractants and pro-survival factors in BM after in vivo exposure to γ-irradiation or cyclophosphamide treatment. Panel A. Real-time PCR analysis of changes in the expression of mRNA for SDF-1 and SF in murine BM 24 hours after irradiation (750 cGy) or exposure to cyclophosphamide (200 mg/kg/bw/mouse). The experiment was repeated three times with four animals/group. Panel B. Mass spectrometry analysis shows that ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) become upregulated in murine BM after conditioning for hematopoietic transplantation by lethal irradiation [17]. The data shown in panels A–B represent the combined results from three independent experiments carried out in triplicate per group.